A study led by the Translational research group in rare diseases, led by Dr. Luisa Botella at the Margarita Salas Center for Biological Research (CIB-CSIC), shows the action of two beta-blocking agents on renal carcinoma cells from von Hippel-Lindau (VHL) patients. The results, published in the Journal of Clinical Medicine, suggest that propranolol and ICI-118,551, the compounds studied, are promising drugs for the treatment of these tumors.
VHL is a hereditary rare disease characterized by the appearance of multiple tumors in different organs throughout the individual's lifespan, with clear cell renal carcinoma being the first cause of death in this disease. In the absence of other treatments, surgery is the only therapeutic option for these patients.
The work of Albiñana et al. shows the action of the beta-blocking agents’ propranolol and ICI-118,551 on renal carcinoma cells from VHL patients and other cell lines. The main therapeutic effects observed are grouped into three. On the one hand, the reduction in cell growth capacity is observed through the activation of apoptosis, the mechanism of programmed cell death. Furthermore, they regulate the expression of proteins such as HIF2-alpha, CAIX, or VEGF, important in the processes of cell division and tumor malignancy. Finally, there is a decrease in the expression of key proteins in inflammation and immune response mechanisms such as NFkB-p65, IL-6, and IL-1β.
Studies have been conducted in in vivo tumor models, as well as tumor analysis in VHL patients with renal carcinomas who have received propranolol as a treatment for retinal hemangioblastomas. The results show that both propranolol (patients and mice) and ICI-551,118 (mice) prevent tumor growth and exert an antiangiogenic effect, slowing down invasiveness and metastasis and producing a normalizing effect of inflammation, avoiding proangiogenic processes.
Together, these studies demonstrate that propranolol and ICI-118,551 are promising drugs for the treatment of VHL-associated clear cell renal cell carcinoma. The results generated in this and previous work by the group have made it possible to designate propranolol as an orphan drug and generated a patent for the use of ICI-118,551 for VHL disease, currently under development by Cycle Pharmaceuticals.
This work is the result of a collaboration between the CIB Margarita Salas and the Spanish Alliance of von Hippel-Lindau families, the University Hospital Fundación Jiménez Díaz, the Italian Hospital of Buenos Aires and the IdiPaz Research Institute.
This research was funded by the Ministry of Economy and Competitivity, the Madrid Regional Government “INMUNOTHERCAN” project, the Spanish Alliance of VHL patients, and CIBERER-ISCIII.
Reference: “Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease”. Albiñana V, Gallardo-Vara E, de Rojas-P I, Recio-Poveda L, Aguado T, Canto-Cano A, Aguirre DT, Serra MM, González-Peramato P, Martínez-Piñeiro L, Cuesta AM, Botella LM. (2020) J. Clin. Med. Aug 25;9(9):E2740. doi: 10.3390/jcm9092740